β‐Adrenergic stimulation of C6 glioma cells: effects of cAMP overproduction on cellular metabolites

Pianet, Isabelle; Canioni, Paul; Labouesse, Julie; Merle, M.

doi:10.1111/j.1432-1033.1992.tb17339.x

Cited by 10 publications

(8 citation statements)

References 32 publications

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“…Malignantly transformed astroglia overexpress pharmacologically stimulabe and functionally active β adrenergic receptors [5]. Studies have provided evidence indicating ligand activation of β adrenergic receptor modulated signaling may either promote or blunt proliferation of malignantly transformed cells in glioma models [4,[38][39][40][41][42][43][44] and extra-neuraxial carcinoma [45][46][47][48][49]. Specifically, ligand activation of β adrenergic receptors potently amplifies cellular proliferation in lung [7], gastric [50], hepatocellular [51], pancreatic [52], colorectal [53], breast [54,55], ovarian [56,57], and prostatic [49] carcinoma models in vitro.…”

Section: Modulation Of Cellular Proliferation By β Adrenergic Signalingmentioning

confidence: 99%

RETRACTED ARTICLE: β adrenergic receptor modulated signaling in glioma models: promoting β adrenergic receptor-β arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma

Ghali

2020

Mol Biol Rep

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Neoplastically transformed astrocytes express functionally active cell surface β adrenergic receptors (βARs). Treatment of glioma models in vitro and in vivo with β adrenergic agonists variably amplifies or attenuates cellular proliferation. In the majority of in vivo models, β adrenergic agonists generally reduce cellular proliferation. However, treatment with β adrenergic agonists consistently reduces tumor cell invasive potential, angiogenesis, and metastasis. β adrenergic agonists induced decreases of invasive potential are chiefly mediated through reductions in the expression of matrix metalloproteinases types 2 and 9. Treatment with β adrenergic agonists also clearly reduce tumoral neoangiogenesis, which may represent a putatively useful mechanism to adjuvantly amplify the effects of bevacizumab. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor receptor. We may accordingly designate βagonists to represent an enhancer of bevacizumab. The antiangiogenic effects of β adrenergic agonists may thus effectively render an otherwise borderline effective therapy to generate significant enhancement in clinical outcomes. β adrenergic agonists upregulate expression of the major histocompatibility class II DR alpha gene, effectively potentiating the immunogenicity of tumor cells to tumor surveillance mechanisms. Authors have also demonstrated crossmodal modulation of signaling events downstream from the β adrenergic cell surface receptor and microtubular polymerization and depolymerization. Complex effects and desensitization mechanisms of the β adrenergic signaling may putatively represent promising therapeutic targets. Constant stimulation of the β adrenergic receptor induces its phosphorylation by β adrenergic receptor kinase (βARK), rendering it a suitable substrate for alternate binding by β arrestins 1 or 2. The binding of a β arrestin to βARK phosphorylated βAR promotes receptor mediated internalization and downregulation of cell surface receptor and contemporaneously generates a cell surface scaffold at the βAR. The scaffold mediated activation of extracellular regulated kinase 1/2, compared with protein kinase A mediated activation, preferentially favors cytosolic retention of ERK1/2 and blunting of nuclear translocation and ensuant pro-transcriptional activity. Thus, βAR desensitization and consequent scaffold assembly effectively retains the cytosolic homeostatic functions of ERK1/2 while inhibiting its pro-proliferative effects. We suggest these mechanisms specifically will prove quite promising in developing primary and adjuvant therapies mitigating glioma growth, angiogenesis, invasive potential, and angiogenesis. We suggest generating compounds and targeted mutations of the β adrenergic receptor favoring β arrestin binding and scaffold facilitated activation of ERK1/2 may hold potential promise and therapeutic benefit in adjuvantly treating most or all cancers. We hope our discussion will generate fruitful research endeavors seeking to exploit these mechanisms.

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Section: Modulation Of Cellular Proliferation By β Adrenergic Signalingmentioning

confidence: 99%

RETRACTED ARTICLE: β adrenergic receptor modulated signaling in glioma models: promoting β adrenergic receptor-β arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma

Ghali

2020

Mol Biol Rep

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“…Their experimental use might be useful to study several aspects of metabolic modulation in astrocytes. In particular, glutamine synthetase represents a potential strategic target for hormonal regulation, 255 and its activity is also increased by trophic factors released by surrounding neurons.…”

Section: Manganese Neurotoxicitymentioning

confidence: 99%

“…94,194,255 Insulin and insulin-like growth factors (IGFs), for example, are suggested to have a neuromodulatory role in the brain. Insulin and IGF-1 had similar effects on mitochondria but individual effects on cytosolic glucose metabolism.…”

Section: Manganese Neurotoxicitymentioning

confidence: 99%

Regulation of glial metabolism studied by ¹³C‐NMR

Zwingmann¹,

Leibfritz²

2003

NMR in Biomedicine

107

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Glial metabolism and their metabolic trafficking with neurons are essential parts of neuronal function, as they modulate, by this means, neuronal activity. Ex vivo and in vitro 13 C-NMR spectroscopy have been used to monitor neural cellular and tissue metabolism. Special emphasis has been given to the metabolic specialization of astrocytes and its enzymatic regulation. For this purpose primary cell cultures are useful tools to study neuronal-glial metabolic relationships as the extracellular fluid can be investigated and manipulated by various stimuli. In astrocytes, glucose is utilized predominantly anaerobically. Glycolysis is interrelated to the astrocytic TCA cycle via bi-directional signals and metabolic exchange processes between astrocytes and neurons. Besides glucose oxidation, neuronally released glutamate is metabolized through the glial TCA cycle. The flexibility of glutamate metabolism, depending on ammonia and energy homeostasis, and the discovered pyruvate recycling pathway in astrocytes, modulates the glutamine-glutamate cycle. 13 C-NMR studies have extended the concept of the 'non-stoichiometric' glutamate-glutamine cycle between neurons and astrocytes. An alanine-lactate shuttle between neurons and astrocytes contributes to nitrogen transfer from neurons to astrocytes, recycles energy substrates for neurons, and in return promotes intercellular glutamine-glutamate cycling. The conversion of alanine to lactate in astrocytes is regulated by intracytosolic pyruvate compartmentation. In essence, the metabolic flexibility and compartmentalized enzymatic specialization of astrocytes buffers the brain tissue against metabolic impairments and excitotoxicity in response to extracellular stimuli, some of them being released by neurons. These in vitro studies using 13 C-NMR spectroscopy provide important knowledge regarding physiological and pathophysiological regulation of neural metabolism to improve our understanding of general brain function.

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“…Experiments with melanocytes (Degani et al 1991) and C6 glioma cells (Pianet et al 1992) unexpectedly revealed that phosphoethanolamine (PEt) levels increased during agonist stimulation of the cells. These results suggest that there is an unknown signal-transduction system mediated by hydrolysis of phosphatidylethanolamine generating PEt, which is known to act as a cholinergic enhancing factor (Bostwick et al 1989).…”

Section: Phosphoinositide Systemmentioning

confidence: 99%